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Initial Findings of Striatum Tripartite Model in OCD Brain Samples Based www.nature.com/scientificreports OPEN Initial fndings of striatum tripartite model in OCD brain samples based on transcriptome analysis Received: 1 May 2018 Bianca C. G. Lisboa1, Katia C. Oliveira1, Ana Carolina Tahira 1, André Rocha Barbosa1,2, Accepted: 17 December 2018 Arthur Sant’Anna Feltrin3, Gisele Gouveia1, Luzia Lima1, Ana Cecília Feio dos Santos 1, Published: xx xx xxxx David Correa Martins Jr.3, Renato David Puga4, Ariane Cristine Moretto1, Carlos Alberto De Bragança Pereira2, Beny Lafer1, Renata Elaine Paraizo Leite1, Renata Eloah De Lucena Ferretti-Rebustini1, Jose Marcelo Farfel1, Lea Tenenholz Grinberg1,5, Wilson Jacob-Filho1, Euripedes Constantino Miguel1, Marcelo Queiroz Hoexter1 & Helena Brentani1,2 Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by obsessions and/or compulsions. Diferent striatal subregions belonging to the cortico-striato-thalamic circuitry (CSTC) play an important role in the pathophysiology of OCD. The transcriptomes of 3 separate striatal areas (putamen (PT), caudate nucleus (CN) and accumbens nucleus (NAC)) from postmortem brain tissue were compared between 6 OCD and 8 control cases. In addition to network connectivity deregulation, diferent biological processes are specifc to each striatum region according to the tripartite model of the striatum and contribute in various ways to OCD pathophysiology. Specifcally, regulation of neurotransmitter levels and presynaptic processes involved in chemical synaptic transmission were shared between NAC and PT. The Gene Ontology terms cellular response to chemical stimulus, response to external stimulus, response to organic substance, regulation of synaptic plasticity, and modulation of synaptic transmission were shared between CN and PT. Most genes harboring common and/or rare variants previously associated with OCD that were diferentially expressed or part of a least preserved coexpression module in our study also suggest striatum subregion specifcity. At the transcriptional level, our study supports diferences in the 3 circuit CSTC model associated with OCD. Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by obsessions and/or compulsions that are time consuming, distressing, or impair daily function and are not the direct result of a medical condition or substance use; the worldwide prevalence of OCD is 2–3%1. Family studies revealed OCD aggregation patterns; according to twin studies, the heritability of OCD is approximately 40%2,3. More recently, genome-wide asso- ciation studies (GWAS)4,5 suggested that common variation in the heritability of OCD is between 25 and 30%, indicating an important contribution of single nucleotide polymorphisms (SNPs) with a minor frequency allele (MAF) of 5%. Meta-analysis of GWAS in OCD cases and controls6 as well as GWAS in obsessive-compulsive symptoms (OCS) in a population cohort7 studying polygenic risk scores (PRS) corroborate the importance of common variants explaining the phenotypic variance in OCD. Not all GWAS have found SNPs that are signif- cant at the genomic level, but all have found marginally associated SNPs. Some of these SNPs are characterized as methylation quantitative trait loci (mQTLs) and expression quantitative trait loci (eQTLs) in brain areas4,5, while ENCODE/ROADMAP data suggested that other SNPs located in genome regions have regulatory poten- tial6. Copy number variations (CNVs) as well as exome studies examining a higher burden of de novo variations for the involvement of very rare variations in OCD have also been performed8–11. Using an innovative statistical approach and integrating information from animal studies and targeting both coding and regulatory regions, 1Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil. 2Inter-institutional Grad Program on Bioinformatics, University of Sao Paulo, Sao Paulo, SP, Brazil. 3Center of Mathematics, Computation and Cognition, Federal University of ABC, Santo Andre, SP, Brazil. 4Academic Research Organization–Hospital Israelita Albert Einstein, Sao Paulo, SP, Brazil. 5Memory and Aging Center University of California, San Francisco, USA. Bianca C. G. Lisboa and Katia C. Oliveira contributed equally. Correspondence and requests for materials should be addressed to H.B. (email: [email protected]) SCIENTIFIC REPORTS | (2019) 9:3086 | https://doi.org/10.1038/s41598-019-38965-1 1 www.nature.com/scientificreports/ www.nature.com/scientificreports Hyun Ji Noh et al.12 recently found functional variants associated with OCD. Based on Gene Ontology (GO) enrichment analysis and gene network analysis performed in the majority of the above studies, glutamate signal- ing, synaptic connectivity, and cortico-striato-thalamic circuitry (CSTC) are important in OCD pathophysiology. Tree smaller circuitries from diferent striatal subregions encompassing CSTC may play an important role in the pathophysiology of OCD13,14; the main characteristics of CSTC are the innervation of the frontal cortex towards the striatum (caudate nucleus (CN), putamen (PT) and accumbens nucleus (NAC))14,15. Each small cir- cuitry has specifc characteristics, including afective and limbic, cognitive and dorsal associative, and ventral and motor. Additionally, the relation between the brain regions, paradigms and symptoms of OCD have been explored by neuropsychological tests associated with neuroimaging investigations16. Accordingly, distinct emo- tional or cognitive impairments associated with OCD have been described with its brain signatures17. In addition to symptomatic evidence involving diferent striatum areas associated with OCD, the striatum tri- partite model and connectivity were defned by gene expression18. Tis validation of these small circuits has been demonstrated by delineating distinct striatum subregions based on connectivity using difusion-weighted imag- ing (DWI) data. Te authors parcellated striatum masks by grouping seed voxels with similar profles of extrinsic whole-brain connectivity using k-means clustering. Ten, the authors showed that these striatum subregions can be distinguished with high accuracy based on their gene expression profle. Dopamine receptor signaling and response to amphetamine were important sources of transcript variation separating the dorsal and ventral subre- gions of the striatum, while transcripts associated with glutamate secretion and metabolic processes separated the caudal subregion18. A recent paper compared the transcriptome of brain striatum subregions from controls and cases of Tourette syndrome (TS), which is ofen comorbid with OCD and has also been associated with CSTC19. In diferentially expressed genes (DEGs) and coexpression module analyses, the authors found enrichment for interneuron signaling, neuronal catabolism, microglia signaling and astrocyte metabolism, but they analyzed the CN and PT together19. As diferent areas of the striatum have transcriptome signatures and each area is more associated with a dif- ferent portion of CSTC involved in the pathophysiology of OCD, we expected to fnd specifc molecular profles deregulated in striatum subregions by comparing OCD cases and controls. At the transcriptional level, these fndings could corroborate and better explain the participation of these subregions in diferent circuitries involved in OCD. OCD is a polygenic multifactorial disorder characterized by multiple afected genes working in gene net- works; thus, using only single measures of DEGs cannot reveal deregulation of the activity observed in complex systems20. Accordingly, we searched DEGs and nonpreserved coexpressed modules to explore quantitative and qualitative diferences in the striatum tripartite model in OCD. In addition, we determined if genes previously associated with OCD by prior large-scale genomic studies were represented in diferent striatum subregion com- parisons, contributing to possible functional roles of diferent genetic variants. To our knowledge, this report represents the frst striatal postmortem OCD transcriptome study. Results General population characteristics. Samples were collected between October 2008 and June 2013. A total of 109 cases were screened as potential cases of psychiatric disorders. Seventy-two cases were assigned to the psychiatric group, and 37 cases were placed in the control group. Within the psychiatric group, the fnal diagnosis was OCD in 22 cases, and the remaining 50 cases were diagnosed with psychiatric disorders (bipolar disorder 19, major depression 16, TS 10, schizophrenia 2 and others 3) (Supplementary Fig. 1). Of the 22 OCD cases, 8 had the best estimate diagnosis and all striatum areas, but only 6 OCD cases had viable tissue for our investigation. Finally, we selected 8 controls (Table 1) for these 6 OCD cases matched by age, sex and laterality that had CN, PT and NAC subregion samples available (Supplementary Table 1). Supplementary Table 2 presents descriptions of all OCD cases. Diferential expression. Te transcriptome of 42 brain samples of 3 striatum regions (CN, PT and NAC) from 6 OCD cases and 8 controls was investigated using high-throughput technology, resulting in 2.57 billion paired-end reads (avg. 61 million per sample). A total of 2.42 billion (92.5%) reads were aligned to the genome. Diferential expression in each striatal region was obtained according to the expression of genes in each region, including CN (n = 44,815, with 17,972 Ensembl genes), NAC (n = 45,701, with 18,126 Ensembl genes) and PT (n = 45,470 with 17,886 Ensembl genes). Most parts of the assembled
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